Homeostasis requires signaling between cells to coordinate activities such as cellular proliferation and differentiation. Inappropriate signaling can cause or exacerbate immune system pathologies, such as allergies, autoimmune diseases, and inflammation, as well as neurological and cardiovascular maladies. In particular, cancer, the uncontrolled proliferation of cells, is strongly associated with breakdown in normal cellular signaling. Signaling often involves catalyzed transfer of phosphoryl groups to and from serine, threonine, and tyrosine residues on proteins as part of signal transduction, a step catalyzed by enzymes called protein kinases. For this reason, efforts to treat cancer and other diseases have directed attention to inhibition of protein kinases.
CK2, an essential serine/threonine protein kinase, until recently has not been considered as a possible target in cancer chemotherapy, but a wide variety of cancers exhibit elevated levels of CK2 activity that correlate with the aggressiveness of tumor growth. Furthermore, decreasing CK2 activity, through use of small molecules, dominant negative overexpression of kinase inactive mutants, anti-sense methods, or small interfering RNAs, decreases cellular proliferation, increases the level of apoptosis in cancer cells, and eradicates the PC3 human prostate cancer cells from tumor-bearing mice. Existing C2 inhibitors such as emodin, coumarins, TBB (triazole), quinazolines, DRB and quercetin, however, while useful for laboratory studies, lack the qualities of a clinically useful chemotherapeutic agent.
A need remains, therefore, for compounds that inhibit CK2 activity for treating pathologies associated with phosphorylation catalyzed by this protein kinase.